Multiple Sclerosis (MS) is a progressive and disabling disease of the central nervous system (CNS) affecting more than twice as many women as men (1-4). Evidence suggests that neuronal damage begins early in MS (5), with acute axonal injury already present during active demyelination. However, remyelination is known to occur in MS (6,7) where it protects against axon loss (8). Indeed no significant axonal damage can be observed in remyelinated plaques (5). Axons become less receptive to remyelination as MS progresses.
MS is an inflammatory disease in which the fatty myelin sheath around the axons of the brain and spinal chord are damaged leading to demyelination and scarring, as well as a broad spectrum of signs and symptoms. In particular, MS effects the ability of nerve cells in the brain and spinal chord to communicate with each other. When myelin is lost the axons can no longer effectively conduct signals. MS itself effects both male and female patients.
Present pharmacological treatments of multiple sclerosis (MS) are limited to immunomodulatory and anti-inflammatory drugs, which are only palliative and do not significantly slow the progress of the disease (12).
An effective treatment strategy for MS must also include therapeutic agents that reverse axon demyelination in order to prevent irreversible axon loss. Testosterone, a male sex hormone, may have beneficial effects on MS and neuroprotection. (9)
However, stimulating the endogenous capacity of myelin repair has remained an unmet but significant therapeutic need (13). Indeed, myelin can be extensively repaired as part of a natural healing process during early stages of MS, explaining why in most cases the disease starts with a relapsing/remitting course. However, the capacity for myelin repair then progressively decreases, and the disease becomes progressively worse. Moreover, the efficiency of myelin repair markedly differs among patients, and although the prevalence of MS in females is higher compared to that of males, male MS patients generally reach disability milestones earlier than women, and males are associated with more rapid progression of the disease and a worse outcome (14).
7α-methyl-19-nortestosterone (MENT) is a different potent synthetic androgen which does not undergo 5α reduction and has therefore been investigated for long-term clinical use particularly because it is less stimulatory to the prostate. MENT itself has been recognized as useful, for example, in male contraception (10), as well as in maintaining sexual behavior and mood in hypogonadal men (11). MENT has been shown to be 10 to 12 times as active as testosterone on male targets (15). For example, U.S. Pat. No. 6,767,902 discloses methods of male contraceptive by administering MENT and its pharmaceutically acceptable salts, preferably as the sole sperm suppressive agent administered to males for this purpose.
Another known androgen is 5α-dihydrotestosterone or DHT. Indeed, DHT has about three times greater affinity for androgen receptors than does testosterone. DHT is possibly best known for its roles in causing male pattern hair loss and prostate problems. Another known androgen metabolite is estradiol, primarily known as the predominant sex hormone present in females. However, it is also present in males and is a metabolite product of testosterone.
Moreover, estrogens have previously been documented to have neuroprotective and anti-inflammatory effects in experimental models of MS (17). In addition, it has also been discovered that androgen therapy may also offer therapeutic benefits for diseases of myelin other than MS, in particular for leukodystrophies (18).